Sustained release dosage forms have found wide usage in a variety of technology areas, such as in personal care or agricultural applications, water treatment and particularly in pharmaceutical applications. Sustained release dosage forms are designed to release a finite quantity of a compound into an aqueous environment over an extended period of time. Known sustained release pharmaceutical dosage forms contain a medicament or a vitamin whose rate of release is controlled by a polymeric matrix. Sustained release pharmaceutical dosage forms are desirable because they provide a method of delivering a long-lasting dose in a single application without overdosing. U.S. Pat. No. 4,734,285 discloses that the release of an active composition from a solid tablet can be prolonged by employing a fine particle sized hydroxypropyl methylcellulose ether composition. The particle size of the hydroxypropyl methylcellulose ether is so small that at least 90 percent by weight of the cellulose ether particles pass through a 100 mesh screen, and preferably at least 97 percent by weight of the cellulose ether particles pass through a 140 mesh screen to achieve a long release profile. While such hydroxypropyl methylcellulose ether particles provide excellent release profiles to tablets, these particles of very small size are known to be of poor flowability and to increase the risk of dust inhalation or dust explosions.
In order to prepare solid, shaped dosage forms from powders, it is generally necessary to process the powders in a manner to improve their flowability and other characteristics which will enable the resulting material to be fabricated by conventional processes such as tableting, encapsulation, molding, etc. into a satisfactory unit form that can suitably deliver an active substance, such as a therapeutic agent, into the environment of use.
Various processes have therefore been developed for modifying powders or other particulate materials, in which typically the powders are gathered together with a binder material into larger permanent free-flowing agglomerates or granules referred to collectively as a “granulation.” Granular materials provide the benefits of improved dry flow properties, reduced dusting and in many cases increased dispersibility when preparing solutions.
For example, solvent-assisted “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions that result in formation of a wet granulated mass from which the solvent must then be evaporated. Such processes, while widely employed, have certain recognized limitations, for example in connection with moisture or heat sensitive medicaments or other actives. Alternatively, the known “dry granulation” processes, which can depend on fairly complicated milling schemes to produce a suitable granulation, also have acknowledged disadvantages.
A direct compression process can provide a simpler and more economical means of preparing compressed dosage forms. In such a process, the active ingredient, such as biologically active ingredients like vitamins, herbal and mineral supplements and drugs, is combined with an excipient, i.e., a substance which does not serve as an active ingredient and does not have a therapeutic effect, but is used as a diluent, vehicle or binder for the active ingredient and which itself is characterized in having the requisite properties for tableting, such as flowability, appropriate particle size distribution, binding ability, acceptable bulk and tap density and/or dissolution properties. The resulting blend can therefore be directly provided to a die cavity or mold for compaction, without prior granulation. See Shangraw, “Compressed Tablets by Direct Compression,” in Pharmaceutical Dosage Forms, 2d Ed., 1989, Vol. 1, pp. 195-246. The resulting compressed dosage form generally provides the requisite stability, dissolution or disintegration properties, tablet-to-tablet and batch uniformity and other desirable characteristics of solid dosage forms.
Materials employed by the art which to varying degrees fulfill the requirements of a direct compression vehicle include water soluble materials e.g., various forms of lactose, such as spray-dried lactose, Fast Flow (Trademark) lactose, or anhydrous lactose, as well as sucrose, dextrose, sorbitol, mannitol and maltodextrin, and relatively insoluble materials such as microcrystalline cellulose, such as Avicel™, starch, dicalcium phosphate dihydrate, and calcium carbonate. U.S. Pat. No. 5,237,758 discloses the use of directly compressible polyethylene oxide vehicles for preparing directly compressible therapeutic dosage forms. U.S. Pat. No. 4,159,345 discloses the use of a microcrystalline cellulose having an average degree of polymerization of 60 to 375, an apparent specific volume of 1.6 to 3.1 cc/g, and a repose angle of 35 to 42° as an excipient in high-speed direct compression. Furthermore, it is known to use fumed silica as a glidant in tablet and capsule formulations to promote the flow of powders.
One object of the present invention is to provide a granular material which has good flowability and which is useful as an excipient for dosage forms, particularly for preparing tablets of suitable hardness. A preferred object of the present invention is to provide a granular material which is useful as an excipient for dosage forms and which has the combined properties of good flowability and the ability to delay and/or control (sustain) the release of an active ingredient from the dosage form. An even more preferred object of the present invention is to provide a granular material which is useful as an excipient for a dosage form, which has the above-mentioned properties of good flowability and ability of sustained release and which is useful in a direct compression process for producing dosage forms.